5-halogen-substituted oxindole derivatives and use thereof for treating vasopressin-dependent diseases

ABSTRACT

The present invention relates to novel 5-halogen-substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is the U.S. national stage entry of International PatentApplication No. PCT/EP2008/066934, filed on Dec. 5, 2008, which claimspriority to U.S. Provisional Patent Application No. 61/012,234, filedDec. 7, 2007, the contents of all of which are hereby incorporated byreference.

Vasopressin is an endogenous hormone which exerts various effects onorgans and tissues. It is suspected that the vasopressin system isinvolved in various pathological states such as, for example, heartfailure and high blood pressure. At present, three receptors (V1a, V1bor V3 and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore being investigatedas possible new therapeutic approaches for the treatment of diseases (M.Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740).

Novel substituted oxindoles having a phenylsulfonyl group in position 1are described herein. 1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones havepreviously been described as ligands of vasopressin receptors. WO93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO01/164668 and WO 01/98295 also describe derivatives having arylsulfonylgroups in position 1 of the oxindole structure. These compounds differfrom the compounds of the invention essentially through the substituentsin position 3.

Thus, WO 93/15051 and WO 98/25901 describe1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones, in which the oxindolestructure is substituted in position 3 by two alkyl radicals which mayalso together form a cycloalkyl radical (spiro linkage), as ligands ofvasopressin receptors. As alternative, the spiro ring may compriseheteroatoms such as oxygen and nitrogen (optionally with substituents).

WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-oneshaving a nitrogen atom in position 3 as ligands of vasopressinreceptors. In addition, radicals selected from optionally substitutedalkyl, cycloalkyl, phenyl or benzyl radicals are bonded in position 3.

WO 03/008407 describes 1-phenylsulfonyloxindoles in whichpyridylpiperazines are linked via a urea, carbamate or 2-oxoethyl groupto the oxindole in position 3. WO 2005/030755 describes as example 1055-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate.

WO 2006/005609 describes as example 66 the dihydrochloride of4-(1-methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.

Besides the binding affinity for the vasopressin V1b receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis ofvasopressin-dependent disorders, such as, for example:

-   1.) a selectivity for the vasopressin V1b receptor compared with the    vasopressin V1a receptor, i.e. the quotient of the binding affinity    for the V1a receptor (Ki(V1a) (determined in the unit “nanomolar    (nM)”) and the binding affinity for the V1b receptor (Ki(V1b))    (determined in the unit “nanomolar (nM)”). A larger quotient    Ki(V1a)/Ki(V1b) means a greater V1b selectivity;-   2.) a selectivity for the vasopressin V1b receptor compared with the    vasopressin V2 receptor, i.e. the quotient of the binding affinity    for the V2 receptor (Ki(V2) (determined in the unit “nanomolar    (nM)”) and the binding affinity for the V1b receptor (Ki(V1b))    (determined in the unit “nanomolar (nM)”). A larger quotient    Ki(V2)/Ki(V1b) means a greater V1b selectivity;-   3.) a selectivity for the vasopressin V1b receptor compared with the    oxytocin OT receptor, i.e. the quotient of the binding affinity for    the OT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”)    and the binding affinity for the V1b receptor (Ki(V1b)) (determined    in the unit “nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b)    means a greater V1b selectivity.-   4.) the metabolic stability, for example determined from the    half-lives, measured in vitro, in liver microsomes from various    species (e.g. rat or human);-   5.) no or only low inhibition of cytochrome P450 (CYP) enzymes:    cytochrome P450 (CYP) is the name for a superfamily of heme proteins    having enzymatic activity (oxidase). They are also particularly    important for the degradation (metabolism) of foreign substances    such as drugs or xenobiotics in mammalian organisms. The principal    representatives of the types and subtypes of CYP in the human body    are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors    (e.g. grapefruit juice, cimetidine, erythromycin) are used at the    same time as medicinal substances which are degraded by this enzyme    system and thus compete for the same binding site on the enzyme, the    degradation thereof may be slowed down and thus effects and side    effects of the administered medicinal substance may be undesirably    enhanced;-   6.) a suitable solubility in water (in mg/ml);-   7.) suitable pharmacokinetics (time course of the concentration of    the compound of the invention in plasma or in tissue, for example    brain). The pharmacokinetics can be described by the following    parameters: half-life (in h), volume of distribution (in l·kg⁻¹),    plasma clearance (in l·h⁻¹·kg⁻¹), AUC (area under the curve, area    under the concentration-time curve, in ng·h·l⁻¹), oral    bioavailability (the dose-normalized ratio of AUC after oral    administration and AUC after intravenous administration), the    so-called brain-plasma ratio (the ratio of AUC in brain tissue and    AUC in plasma);-   8.) no or only low blockade of the hERG channel: compounds which    block the hERG channel may cause a prolongation of the QT interval    and thus lead to serious disturbances of cardiac rhythm (for example    so-called “torsade de pointes”). The potential of compounds to block    the hERG channel can be determined by means of the displacement    assay with radiolabelled dofetilide which is described in the    literature (G. J. Diaz et al., Journal of Pharmacological and    Toxicological Methods, 50 (2004), 187-199). A smaller IC50 in this    dofetilide assay means a greater probability of potent hERG    blockade. In addition, the blockade of the hERG channel can be    measured by electrophysiological experiments on cells which have    been transfected with the hERG channel, by so-called whole-cell    patch clamping (G. J. Diaz et al., Journal of Pharmacological and    Toxicological Methods, 50 (2004), 187-199).

It was therefore an object of the present invention to provide compoundsfor the treatment or prophylaxis of various vasopressin-dependentdiseases. The compounds were intended to have a high activity andselectivity, especially a high affinity and selectivity vis-à-vis thevasopressin V1b receptor. In addition, the substance of the inventionwas intended to have one or more of the aforementioned advantages 1.) to8.).

The object is achieved by compounds of the formula I

in which

-   R¹ is hydrogen, methoxy or ethoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl;-   R⁴ is ethoxy or isopropoxy;-   R⁵ is H or methyl;-   R⁶ is Cl or F;-   X¹ is O, NH or CH₂; and-   X² and X³ are N or CH, with the proviso that X² and X³ are not    simultaneously N;    and their pharmaceutically acceptable salts and prodrugs thereof.

Accordingly, the present invention relates to compounds of the formula I(also “compounds I” hereinafter) and the pharmaceutically acceptablesalts of the compounds I and the prodrugs of the compounds I.

The pharmaceutically acceptable salts of compounds of the formula I,which are also referred to as physiologically tolerated salts, areordinarily obtainable by reacting the free base of the compounds I ofthe invention (i.e. of the compounds I according to structural formulaI) with suitable acids. Examples of suitable acids are listed in“Fortschritte der Arzneimittelforschung”, 1966, Birkhauser Verlag, vol.10, pp. 224-285. These include for example hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, formic acid, maleic acid and fumaric acid.

The term “prodrugs” means compounds which are metabolized in vivo to thecompounds I of the invention. Typical examples of prodrugs are describedin C. G. Wermeth (editor): The Practice of Medicinal Chemistry, AcademicPress, San Diego, 1996, pages 671-715. These include for examplephosphates, carbamates, amino acids, esters, amides, peptides, ureas andthe like. Suitable prodrugs in the present case may be for examplecompounds I in which the outer nitrogen atom of the outerpiperidine/piperazine ring forms an amide/peptide linkage by thisnitrogen atom being substituted by a C₁-C₄-alkylcarbonyl group, e.g. byacetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonylor tert-butylcarbonyl (pivaloyl), by benzoyl, or by an amino acidresidue linked via CO, e.g. glycine, alanine, serine, phenylalanine andthe like linked via CO, in the position of the radical R³. Furthersuitable prodrugs are alkylcarbonyloxyalkyl carbamates in which theouter nitrogen atom of the outer piperidine/piperazine ring has in theposition of the radical R³ a group of the formula—C(═O)—O—CHR^(a)—O—C(═O)—R^(b) in which R^(a) and R^(b) areindependently of one another C₁-C₄-alkyl. Such carbamates are describedfor example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J.Medicinal Chem. 1988, 31(2), 318-322. These groups can then beeliminated under metabolic conditions and result in compounds I in whichR³ is H.

C₁-C₄-Alkyl is in the context of the present invention a linear orbranched alkyl radical having 1 to 4 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

C₁-C₃-Alkoxy is in the context of the present invention a linear orbranched alkyl radical linked via an oxygen atom and having 1 to 3carbon atoms. Examples are methoxy, ethoxy, n-propoxy and isopropoxy.

The compounds of the invention of the formula I, their pharmacologicallyacceptable salts and their prodrugs may also be present in the form ofsolvates or hydrates. Solvates mean in the context of the presentinvention crystalline forms of the compounds I or of theirpharmaceutically acceptable salts or prodrugs thereof which comprisesolvent molecules incorporated in the crystal lattice. The solventmolecules are preferably incorporated in stoichiometric ratios. Hydratesare a specific form of solvates; the solvent in this case is water.

The statements made hereinafter concerning suitable and preferredfeatures of the invention, especially concerning the radicals R¹, R²,R³, R⁴, R⁵, R⁶, X¹, X² and X³ in the compound I, but also concerning thefeatures of the process of the invention and of the use according to theinvention apply both taken on their own and preferably in any possiblecombination with one another.

The compounds I are preferably provided in the form of the free base(i.e. according to structural formula I) or in the form of their acidaddition salts.

In a preferred embodiment, R¹ is hydrogen or methoxy.

In a particularly preferred embodiment, R¹ and R² are methoxy.

In a preferred embodiment, R³ is hydrogen, methyl or ethyl, inparticular hydrogen or methyl and is specifically methyl.

In a preferred embodiment, R⁴ is ethoxy and R⁵ is H.

In an alternatively preferred embodiment, R⁴ is ethoxy and R⁵ is methyl.

In an alternatively preferred embodiment, R⁴ is isopropoxy and R⁵ is H.

R⁴ is particularly preferably ethoxy and R⁵ is H.

In a preferred embodiment, R⁶ is Cl.

In an alternatively preferred embodiment, R⁶ is F.

R⁶ is particularly preferably Cl.

In a preferred embodiment, X′ is NH.

In an alternatively preferred embodiment, X′ is O.

In an alternatively preferred embodiment, X′ is CH₂.

X¹ is particularly preferably NH or CH₂ and especially NH.

In a preferred embodiment, one of the variables X², X³ is N and theother is CH.

In a particularly preferred embodiment in this connection, X² is N andX³ is CH.

In an alternatively particularly preferred embodiment, X² is CH and X³is N.

In an alternatively preferred embodiment, both variables X², X³ are CH.

The invention preferably relates to compounds of the formula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl, preferably    hydrogen, methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH, O or CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly preferably relates to compounds of theformula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH, O or CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention more preferably relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH, O or CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates to compounds of the formula Iin which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I in which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH;-   X² is N;-   X³ is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH;-   X² is CH;-   X³ is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH;-   X² is CH;-   X³ is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention preferably relates alternatively to compounds of theformula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl, preferably    hydrogen, methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH, O or CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly preferably relates alternatively to compoundsof the formula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH, O or CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention more preferably relates alternatively to compounds of theformula I in which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH, O or CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention more preferably still relates alternatively to compoundsof the formula I in which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I in which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is CH₂;-   X² is N or CH;-   X³ is N or CH;-   where X² and X³ are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH;-   X² is N;-   X³ is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH;-   X² is CH;-   X³ is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl or ethyl;-   R⁴ is ethoxy;-   R⁵ is methyl;-   R⁶ is Cl;-   X¹ is NH;-   X² is CH;-   X³ is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

Special preference is given to compound I in which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is methyl;-   R⁴ is ethoxy;-   R⁵ is hydrogen;-   R⁶ is Cl;-   X¹ is NH;-   X² is N;-   X³ is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

Examples of preferred embodiment of the present invention are compoundsof the formula 1.1 to 1.18 and the pharmaceutically acceptable salts andprodrugs thereof, in which the radicals X², X³, R¹, R² and R³ assume ineach case the meanings mentioned in each line in the following table 1.

TABLE 1 Example No. X² X³ R¹ R² R³ A-1. N CH Methoxy Methoxy Methyl A-2.N CH Methoxy H Methyl A-3. N CH Ethoxy H Methyl A-4. N CH H H MethylA-5. N CH H Methoxy Methyl A-6. N CH Ethoxy Methoxy Methyl A-7. N CHMethoxy Methoxy Ethyl A-8. N CH Methoxy H Ethyl A-9. N CH Ethoxy H EthylA-10. N CH H H Ethyl A-11. N CH H Methoxy Ethyl A-12. N CH EthoxyMethoxy Ethyl A-13. N CH Methoxy Methoxy n-Propyl A-14. N CH Methoxy Hn-Propyl A-15. N CH Ethoxy H n-Propyl A-16. N CH H H n-Propyl A-17. N CHH Methoxy n-Propyl A-18. N CH Ethoxy Methoxy n-Propyl A-19. N CH MethoxyMethoxy Isopropyl A-20. N CH Methoxy H Isopropyl A-21. N CH Ethoxy HIsopropyl A-22. N CH H H Isopropyl A-23. N CH H Methoxy Isopropyl A-24.N CH Ethoxy Methoxy Isopropyl A-25. N CH Methoxy Methoxy H A-26. N CHMethoxy H H A-27. N CH Ethoxy H H A-28. N CH H H H A-29. N CH H MethoxyH A-30. N CH Ethoxy Methoxy H A-31. CH N Methoxy Methoxy Methyl A-32. CHN Methoxy H Methyl A-33. CH N Ethoxy H Methyl A-34. CH N H H MethylA-35. CH N H Methoxy Methyl A-36. CH N Ethoxy Methoxy Methyl A-37. CH NMethoxy Methoxy Ethyl A-38. CH N Methoxy H Ethyl A-39. CH N Ethoxy HEthyl A-40. CH N H H Ethyl A-41. CH N H Methoxy Ethyl A-42. CH N EthoxyMethoxy Ethyl A-43. CH N Methoxy Methoxy n-Propyl A-44. CH N Methoxy Hn-Propyl A-45. CH N Ethoxy H n-Propyl A-46. CH N H H n-Propyl A-47. CH NH Methoxy n-Propyl A-48. CH N Ethoxy Methoxy n-Propyl A-49. CH N MethoxyMethoxy Isopropyl A-50. CH N Methoxy H Isopropyl A-51. CH N Ethoxy HIsopropyl A-52. CH N H H Isopropyl A-53. CH N H Methoxy Isopropyl A-54.CH N Ethoxy Methoxy Isopropyl A-55. CH N Methoxy Methoxy H A-56. CH NMethoxy H H A-57. CH N Ethoxy H H A-58. CH N H H H A-59. CH N H MethoxyH A-60. CH N Ethoxy Methoxy H A-61. CH CH Methoxy Methoxy Methyl A-62.CH CH Methoxy H Methyl A-63. CH CH Ethoxy H Methyl A-64. CH CH H HMethyl A-65. CH CH H Methoxy Methyl A-66. CH CH Ethoxy Methoxy MethylA-67. CH CH Methoxy Methoxy Ethyl A-68. CH CH Methoxy H Ethyl A-69. CHCH Ethoxy H Ethyl A-70. CH CH H H Ethyl A-71. CH CH H Methoxy EthylA-72. CH CH Ethoxy Methoxy Ethyl A-73. CH CH Methoxy Methoxy n-PropylA-74. CH CH Methoxy H n-Propyl A-75. CH CH Ethoxy H n-Propyl A-76. CH CHH H n-Propyl A-77. CH CH H Methoxy n-Propyl A-78. CH CH Ethoxy Methoxyn-Propyl A-79. CH CH Methoxy Methoxy Isopropyl A-80. CH CH Methoxy HIsopropyl A-81. CH CH Ethoxy H Isopropyl A-82. CH CH H H Isopropyl A-83.CH CH H Methoxy Isopropyl A-84. CH CH Ethoxy Methoxy Isopropyl A-85. CHCH Methoxy Methoxy H A-86. CH CH Methoxy H H A-87. CH CH Ethoxy H HA-88. CH CH H H H A-89. CH CH H Methoxy H A-90. CH CH Ethoxy Methoxy H

The preferred compounds among the compounds I.1 to I.18 mentioned aboveare those of the formulae I.1, I.3, I.5, I.7, I.9, I.11, I.13, I.15 andI.17, in which the radicals X², X³, R¹, R² and R³ assume in each casethe meanings mentioned in each line in table 1. Compounds among thesewhich are in turn preferred are those of the formulae I.1, I.3, I.5, I.7and I.13, in which the radicals X², X³, R¹, R² and R³ assume in eachcase the meanings mentioned in each line in table 1.

Compounds particularly preferred are those of the formula I.1, in whichthe radicals X², X³, R¹, R² and R³ assume in each case the meaningsmentioned in table 1 in lines A-1, A-2, A-4, A-7, A-31, A-32, A-34,A-37, A-38, A-40, A-61, A-67 and A-85, preferably those in lines A-1,A-2, A-4, A-7, A-31, A-37, A-38, A-61 and A-67, and in particular thosein lines A-1, A-4, A-7, A-31, A-37, A-61 and A-67.

Compounds particularly preferred are also those of the formula I.3, inwhich the radicals X², X³, R¹, R² and R³ assume in each case themeanings mentioned in table 1 in lines A-1, A-7, A-31 and A-37, andpreferably those in lines A-1 and A-7.

Particularly preferred compounds are also those of the formula I.5, inwhich the radicals X², X³, R¹, R² and R³ assume in each case themeanings mentioned in table 1 in lines A-1, A-7, A-31 and A-37, andpreferably those in lines A-1 and A-7.

Particularly preferred compounds are also those of the formula 1.7 inwhich the radicals X², X³, R¹, R² and R³ assume in each case themeanings mentioned in table 1 in lines A-1, A-4, A-31, A-34, A-37 andA-40, and preferably in line A-1.

Particularly preferred compounds are also those of the formula 1.13 inwhich the radicals X², X³, R¹, R² and R³ assume in each case themeanings mentioned in table 1 in lines A-1, A-2, A-4, A-31, A-32 andA-34, and preferably in line A-2.

Among these particularly preferred compounds in turn preferred compoundsare I.1, I.3, I.5 and I.7, in which the radicals X², X³, R¹, R² and R³have the meanings indicated for the respective compounds. Particularlypreferred compounds among these are those of the formulae I.1, I.3 andI.5 and especially of the formulae I.1 and I.3, with compounds of theformula I.1 being even more greatly preferred.

The compounds I of the invention have a center of chirality in position3 of the 2-oxindole ring. The compounds of the invention may thereforebe in the form of a 1:1 mixture of enantiomers (racemate) or of anonracemic mixture of enantiomers in which one of the two enantiomers,either the enantiomer which rotates the plane of vibration of linearlypolarized light to the left (i.e. minus rotation) (hereinafter (−)enantiomer) or the enantiomer which rotates the plane of vibration oflinearly polarized light to the right (i.e. plus rotation) (hereinafter(+) enantiomer), is enriched, or of substantially enantiopure compounds,that is to say of substantially enantiopure (−) enantiomer or (+)enantiomer. Since the compounds of the invention have a single center ofasymmetry and no axis/plane of chirality, a nonracemic mixture can alsobe defined as a mixture of enantiomers in which either the R or the Senantiomer predominates. Substantially enantiopure compounds canaccordingly also be defined as substantially enantiopure R enantiomer orsubstantially enantiopure S enantiomer.

“Substantially enantiopure compounds” means in the context of thepresent invention those compounds having an enantiomeric excess (ee; %ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably atleast 85% ee, more preferably at least 90% ee, even more preferably atleast 95% ee and in particular at least 98% ee.

In one embodiment of the invention, the compounds of the invention arein the form of substantially enantiopure compounds. Particularlypreferred compounds have an enantiomeric excess of at least 85% ee, morepreferably of at least 90% ee, even more preferably of at least 95% eeand in particular of at least 98% ee.

The invention thus relates both to the pure enantiomers and to mixturesthereof, e.g. mixtures in which one enantiomer is present in enrichedform, but also to the racemates. The invention also relates to thepharmaceutically acceptable salts and the prodrugs of the pureenantiomers of compounds I, and the mixtures of enantiomers in the formof the pharmaceutically acceptable salts and prodrugs of compounds I.

Preferred embodiments of the invention are compounds of the formula I asdetailed above which are characterized in that they are in opticallyactive form, and the enantiomer of the relevant compound of the formulaI is the one which rotates the plane of vibration of polarized light tothe right (i.e. plus rotation), in the form of a free base, or apharmaceutically acceptable salt or a prodrug thereof. The enantiomerswith dextrorotation or plus rotation of the compounds I are alsoreferred to hereinafter as (+) enantiomers.

Particularly preference is given to compounds of the general formula I,pharmaceutically acceptable salts and their prodrugs as detailed abovein which the corresponding (+) enantiomer is present in an opticalpurity (enantiomeric excess, ee) of more than 50% ee, particularlypreferably of at least 80% ee, more preferably of at least 90% ee andeven more preferably of at least 95% ee and in particular of at least98% ee.

Likewise preferred embodiments of the invention are compounds of thegeneral formula I as detailed above which are characterized in that theyare in optically inactive form, i.e. in the form of the racemate, or inthe form of a pharmaceutically acceptable salt or of a prodrug of theracemate.

The statements made in the context of the present invention concerningthe direction of rotation of polarized light relate preferably to thesigns [(+) or (−)] as determined in chloroform as solvent or inchloroform-containing solvent mixtures, in particular in chloroform.

Examples of synthetic routes for preparing the oxindole derivatives ofthe invention are described below.

The compounds of the invention can be prepared by using methodsdescribed in WO 2005/030755 and WO 2006/005609 for synthesizinganalogous compounds, and the preparation is outlined by way of examplein synthesis schemes 1 to 3. The variables in these synthetic schemeshave the same meanings as in formula I.

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition ofmetallated heterocycles III onto the 3-keto group of the isatins II. Themetallated heterocycles, such as, for example, the correspondingGrignard (Mg) or organyllithium compound, can be obtained in anyconventional way from halogen or hydrocarbon compounds. Examples ofmethods are present in Houben-Weyl, Methoden der Organischen Chemie,vol. 13, 1-2, chapter on Mg and Li compounds. The isatins II are eithercommercially available or were prepared in analogy to methods describedin the literature (Advances in Heterocyclic Chemistry, A. R. Katritzkyand A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil.Chem. Soc. 12, 273-324, 2001).

The 3-hydroxyoxindoles IV can be converted into the compounds V whichhave a leaving group LG′ in position 3, where the leaving group LG′ is aconventional leaving group such as, for example, chlorine or bromide.The intermediate V with for example LG′=chlorine can be prepared bytreating the alcohol IV with thionyl chloride in the presence of a basesuch as, for example, pyridine, in a suitable solvent such as, forexample, dichloromethane.

The compounds V can subsequently be reacted with amines, such as, forexample, ammonia, in a substitution reaction to give the amines VI. Thecompounds VI can subsequently be converted by treatment with sulfonylchlorides VII after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in DMF into thesulfonylated product VIII. The sulfonyl chlorides VII employed caneither be purchased or be prepared by known processes (for example J.Med. Chem. 40, 1149 (1997)).

The compounds of the invention of the general formula I which have aurea group in position 3 can be prepared as described in WO 2005/030755and WO 2006/005609, and shown in synthesis scheme 1, in a two-stageprocess: firstly, the compounds VIII are reacted with phenylchloroformate in the presence of a base such as, for example, pyridineto give the corresponding phenyl carbamate IX.

Subsequent reaction with amines X, where appropriate at elevatedtemperature and with the addition of auxiliary bases such as, forexample, triethylamine or diisopropylethyl-amine, leads to the compoundsof the invention of the general formula (I) with a urea bridge (X¹═NH).The amines X can be either purchased or prepared by methods known fromthe literature. Compounds I of the invention with R³═H can be preparedby using appropriate Boc-protected amines (R³=Boc). The Boc protectivegroup can subsequently be removed, for example by treatment withtrifluoroacetic acid in dichloromethane.

The compounds of the invention of the general formula I having acarbamate group in position 3 (X¹═O) can be prepared as described in WO2006/005609 and shown in synthesis scheme 2: firstly, the 3-hydroxycompound IV is reacted with phenyl chloroformate to give the phenylcarbonate derivatives XIa and/or XIb. The carbamate derivatives XII areobtained with an excess of amine X and can subsequently be convertedunder the usual conditions (deprotonation with a strong base such as,for example, sodium hydride or potassium tert-butoxide in a suitablesolvent such as, for example, DMF, followed by treatment with sulfonylchlorides VII) into the compounds I of the invention with a carbamatebridge.

The compounds of the invention of the general formula I which have a2-oxoethyl group in position 3 (X¹═CH₂) can be prepared as shown insynthesis scheme 3. Introduction of the acetic acid group can take placeas described in WO 2006/005609 in a 4-stage sequence (1. replacement ofthe leaving group LG′ in V by the sodium salt of dimethyl malonate, 2.hydrolysis of the first ester group, 3. thermal decarboxylation, 4.hydrolysis of the second ester group). The amine side chain X can becoupled to the carboxylic acid XV using standard coupling reagents knownin peptide chemistry, such as, for example, EDC(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) and HOBT(1-hydroxybenzotriazole) in a solvent such as, for example,N,N-dimethylformamide. The sulfonylation can take place by deprotonationof the coupling product XVI with a strong base such as, for example,sodium hydride or potassium tert-butoxide, and subsequent treatment withsulfonyl chlorides VII in a solvent such as, for example, DMF, and leadsto the compounds I of the invention with an amide bridge.

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising at least one compound of the general formula Iand/or a pharmaceutically acceptable salt or a prodrug thereof asdetailed above, and a pharmaceutically acceptable carrier. Suitablecarriers depend inter alia on the dosage form of the composition and areknown in principle to the skilled worker. Some suitable carriers aredescribed hereinafter.

A further aspect of the present invention relates to the use ofcompounds of the formula I and/or of pharmaceutically acceptable saltsor prodrugs thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of vasopressin-dependent diseases.

Vasopressin-dependent diseases are those in which the progress of thedisease is at least partly dependent on vasopressin, i.e. diseases whichshow an elevated vasopressin level which may contribute directly orindirectly to the pathological condition. In other words,vasopressin-dependent diseases are those which can be influenced bymodulating the vasopressin receptor, for example by administration of avasopressin receptor ligand (agonist, antagonist, partialantagonist/agonist, inverse agonist etc.).

In a preferred embodiment, the present invention relates to the use ofcompounds of the invention of the formula I or of pharmaceuticallyacceptable salts or prodrugs for the manufacture of a medicament for thetreatment and/or prophylaxis of diseases selected from diabetes, insulinresistance, nocturnal enuresis, incontinence and diseases in whichimpairments of blood clotting occur, and/or for delaying micturition.The term “diabetes” means all types of diabetes, especially diabetesmellitus (including type I and especially type II), diabetes renalis andin particular diabetes insipidus. The types of diabetes are preferablydiabetes mellitus of type II (with insulin resistance) or diabetesinsipidus.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from hypertension, pulmonary hypertension, heartfailure, myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, impairments of the renal system, edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia,Schwartz-Bartter syndrome, impairments of the gastrointestinal tract,gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers,emesis, emesis occurring during chemotherapy, and travel sickness.

The compounds of the invention of the formula I or theirpharmaceutically acceptable salts or prodrugs or the pharmaceuticalcomposition of the invention can also be used for the treatment ofvarious vasopressin-dependent complaints which have central nervouscauses or alterations in the HPA axis (hypothalamic pituitary adrenalaxis), for example for affective disorders such as depressive disordersand bipolar disorders. These include for example dysthymic disorders,phobias, post-traumatic stress disorders, general anxiety disorders,panic disorders, major depression, seasonal depression and sleepdisorders.

The compounds of the invention of the formula I and theirpharmaceutically acceptable salts or prodrugs or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentof anxiety disorders and stress-dependent anxiety disorders, such as,for example, generalized anxiety disorders, phobias, post-traumaticanxiety disorders, panic anxiety disorders, obsessive-compulsive anxietydisorders, acute stress-dependent anxiety disorders and social phobia.

The compounds of the invention can furthermore also be employed for thetreatment of memory impairments, Alzheimer's disease, psychoses,psychotic disorders, sleep disorders and/or Cushing's syndrome, and allstress-dependent diseases.

Accordingly, a further preferred embodiment of the present inventionrelates to the use of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of affective disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of anxiety disordersand/or stress-dependent anxiety disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of memory impairmentsand/or Alzheimer's disease.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of psychoses and/orpsychotic disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of Cushing's syndrome orother stress-dependent diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of sleep disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of depressive disorders. Aparticular form of depressive disorders are so-called childhood onsetmood disorders, i.e. depressive moods having their onset in childhood.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of vasomotor symptomsand/or thermoregulatory dysfunctions such as, for example, the hot flushsymptom.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis of drugor pharmaceutical dependencies and/or dependencies mediated by otherfactors, for the treatment and/or prophylaxis of stress caused bywithdrawal of one or more factors mediating the dependence and/or forthe treatment and/or prophylaxis of stress-induced relapses into drug orpharmaceutical dependencies and/or dependencies mediated by otherfactors.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofschizophrenia and/or psychosis.

A further aspect of the invention relates to a method for the treatmentand/or prophylaxis of vasopressin-dependent diseases, in which aneffective amount of at least one compound of the invention of theformula I or of at least one pharmaceutically acceptable salt or oneprodrug thereof or of a pharmaceutical composition of the invention isadministered to a patient.

Concerning the definition of vasopressin-dependent diseases, referenceis made to the above statements.

In a preferred embodiment of the invention, the method of the inventionserves for the treatment and/or prophylaxis of disorders selected fromdiabetes, insulin resistance, nocturnal enuresis, incontinence anddiseases in which impairments of blood clotting occur, and/or fordelaying micturition. Concerning the definition of diabetes, referenceis made to the above statements.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of disorders selected fromhypertension, pulmonary hypertension, heart failure, myocardialinfarction, coronary spasm, unstable angina, PTCA (percutaneoustransluminal coronary angioplasty), ischemias of the heart, impairmentsof the renal system, edemas, renal vasospasm, necrosis of the renalcortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome,impairments of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurringduring chemotherapy, and travel sickness.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of affective disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of anxiety disorders and/orstress-dependent anxiety disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of memory impairments and/orAlzheimer's disease.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of psychoses and/or psychoticdisorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of Cushing's syndrome.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of sleep disorders in a patient.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of depressive disorders. In thecase of depressive disorders, specific mention is also to be made ofchildhood onset mood disorders, i.e. depressive moods having their onsetin childhood.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of vasomotor symptoms and/orthermoregulatory dysfunctions, such as, for example, the hot flushsymptom.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of drug or pharmaceuticaldependencies and/or dependencies mediated by other factors, for thetreatment and/or prophylaxis of stress caused by withdrawal of one ormore factors mediating the dependence, and/or for the treatment and/orprophylaxis of stress-induced relapses into drug or pharmaceuticaldependencies and/or dependencies mediated by other factors.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of schizophrenia and/or psychosis.

The patient to be treated prophylactically or therapeutically with themethod of the invention is preferably a mammal, for example a human or anonhuman mammal or a nonhuman transgenic mammal. Specifically it is ahuman.

The compounds of the general formula I, their pharmaceuticallyacceptable salts and prodrugs as detailed above can be prepared by askilled worker with knowledge of the technical teaching of the inventionin implementing and/or in analogous implementation of process stepsknown per se.

The compounds I or their prodrugs and/or their pharmaceuticallyacceptable salts are distinguished by having a selectivity for thevasopressin V1b receptor subtype vis-à-vis at least one of the closelyrelated vasopressin/oxytocin receptor subtypes (for example vasopressinV1a, vasopressin V2 and/or oxytocin).

Alternatively, or preferably in addition, the compounds I or theirprodrugs and/or their pharmaceutically acceptable salts aredistinguished by having an improved metabolic stability.

The metabolic stability of a compound can be measured for example byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (RS Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible in this connection toconclude from an observed longer half-life that the metabolic stabilityof the compound is improved. The stability in the presence of humanliver microsomes is of particular interest because it makes it possibleto predict the metabolic degradation of the compound in the human liver.Compounds with increased metabolic stability (measured in the livermicrosome test) are therefore probably also degraded more slowly in theliver. The slower metabolic degradation in the liver may lead to higherand/or longer-lasting concentrations (active levels) of the compound inthe body, so that the elimination half-life of the compounds of theinvention is increased. Increased and/or longer-lasting active levelsmay lead to a better activity of the compound in the treatment orprophylaxis of various vasopressin-dependent diseases. In addition, animproved metabolic stability may lead to an increased bioavailabilityafter oral administration, because the compound is subject, afterabsorption in the intestine, to less metabolic degradation in the liver(so-called first pass effect). An increased oral bioavailability may,owing to an increased concentration (active level) of the compound, leadto a better activity of the compound after oral administration.

The compounds of the invention are effective after administration byvarious routes. Possible examples are intravenous, intramuscular,subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal,rectal, sublingual, buccal or oral administration, and administration isfrequently intravenous, intramuscular or, in particular, oral.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound I of the invention, of apharmaceutically acceptable salt or of a prodrug thereof and suitablepharmaceutical carriers (drug carriers).

These drug carriers are chosen according to the pharmaceutical form andthe desired mode of administration and are known in principle to theskilled worker.

The compounds of the invention of the formula I or optionally suitablesalts of these compounds can be used to produce pharmaceuticalcompositions for oral, sublingual, buccal, subcutaneous, intramuscular,intravenous, topical, intratracheal, intranasal, transdermal, vaginal orrectal administration, and be administered to animals or humans inuniform administration forms, mixed with conventional pharmaceuticalcarriers, for the prophylaxis or treatment of the above disorders ordiseases.

The suitable administration forms (dose units) include forms for oraladministration such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, forms ofsubcutaneous, intramuscular or intravenous administration and forms ofrectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active ingredient can vary between 0.01 and 50 mg per kg ofbody weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose can be administered once to 5 times a day, sothat a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the activeingredient is mixed with a solid pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display asustained or delayed activity and to release a predetermined amount ofthe active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and including the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may contain active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloringsubstance.

Water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal or vaginal administration is achieved by using suppositorieswhich are prepared with binders which melt at rectal temperature, forexample cocoa butter or polyethylene glycols. Parenteral administrationis effected by using aqueous suspensions, isotonic saline solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The active ingredient may also be formulated as microcapsules orcentrosomes, if suitable with one or more carriers or additives.

The compositions of the invention may, in addition to the compounds ofthe invention, comprise other active ingredients which may be beneficialfor the treatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active ingredients are presenttogether, where at least one of these is a compound I of the invention,salt or a prodrug thereof.

The invention is explained in more detail below by means of examples,but the examples are not to be understood to be restrictive.

The compounds of the invention can be prepared by various syntheticroutes. The methods mentioned, as described accordingly in synthesisschemes 1, 2 and 3, are explained in greater detail merely by way ofexample using the given examples without being exclusively restricted tosynthesis routes 1, 2 or 3 or analogous methods.

EXPERIMENTAL SECTION

Abbreviations used:

-   THF: Tetrahydrofuran-   DMSO: Dimethyl sulfoxide-   TFA: Trifluoroacetic acid-   p: pseudo (for example pt pseudo triplet)-   b: broad (for example bs broad singlet)-   s: singlet-   d: doublet-   t: triplet-   m: multiplet-   dd: doublet of doublets-   dt: doublet of triplets-   tt: triplet of triplets    I. Preparation of the Starting Compounds    a) 3-Hydroxyindoles of the General Formula IV

a.1 5-Chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one

Formation of the sodium salt of isatin: 3.21 g (80.3 mmol) of sodiumhydride (60% in mineral oil) were added in portions to 13.9 g (76.5mmol) of 5-chloroisatin in 300 ml of THF at 0° C., and the mixture wasstirred at 0° C. for one hour.

Formation of the Grignard reagent: ethylmagnesium bromide (95.6 mmol,95.6 ml of a 1M solution in THF) was added dropwise to a solution of2-ethoxy-3-iodopyridine (20.0 g, 80.3 mmol) in 250 ml of THF keeping thetemperature at between 15 and 22° C. The mixture was then stirred atroom temperature for 15 min.

Grignard addition: the solution of the Grignard reagent was pumped intothe ice-cooled solution of the sodium salt of isatin, and the reactionmixture was then stirred at room temperature for three hours. Themixture was poured into 10% ammonium chloride solution and extractedthree times with ethyl acetate. The combined organic phases were washedwith water and saturated brine, dried with magnesium sulfate andconcentrated under reduced pressure. The crystalline precipitate whichhad formed after standing overnight at room temperature was filtered offwith suction and washed with ethyl acetate. 13.3 g of the title compoundwere obtained as a reddish solid.

ESI-MS [M+H⁺]=305 (Cl isotope pattern)

a.25-Chloro-3-(2-ethoxy-5-methylpyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one

Formation of the isatin sodium salt: 1.01 g (27.5 mmol) of sodiumhydride (60% in mineral oil) was added in portions to 5.0 g (27.5 mmol)of 5-chloroisatin in 100 ml of THF at 0° C., and the mixture was stirredat 0° C. for one hour.

Formation of the lithium reagent: n-butyllithium (37.2 mmol, 23.2 ml ofa 1.6M solution in hexane) was added dropwise to a solution, cooled to−78° C., of 3-bromo-2-ethoxy-5-methylpyridine (7.74 g, 35.8 mmol) in 100ml of THF, keeping the temperature below −60° C., and the reactionmixture was then stirred in an acetone/dry ice bath for a further 15min.

Addition: The solution, cooled to −78° C., of the lithiated pyridine waspumped by means of a transfer needle into the ice-cooled solution of theisatin sodium salt, and the reaction mixture was then stirred at roomtemperature for 3 hours. The reaction mixture was poured into 10%ammonium chloride solution and extracted three times with ethyl acetate.The combined organic phases were washed with water and saturated brine,dried over magnesium sulfate and concentrated under reduced pressure.After treatment of the residue with dichloromethane, a beige precipitateformed and was filtered off with suction and washed withdichloromethane. 2.61 g of the title compound were obtained as a reddishsolid.

ESI-MS [M+H⁺]=319 (Cl isotope pattern).

a.35-Chloro-3-(2-isopropoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one

The title compound was prepared in analogy to the process of example a.1using 3-iodo-2-isopropoxypyridine.

b) Amines of the General Formula X

b.1 1-Ethyl-4-piperidin-4-yl-piperazine b.1.1 tert-Butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

29.2 g (256 mmol) of N-ethylpiperazine were introduced with 50.0 g (256mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (corresponds to1-Boc-4-piperidone) into 800 ml of ethanol while cooling in ice. 15.4 g(256 mmol) of glacial acetic acid were added. Then 16.1 g (256 mmol) ofsodium acetoxyborohydride were added in portions to the cooled reactionmixture. Initially slight gas formation was observed and, after additionof ⅔ of the reducing agent, foam formation was observed. The reactionmixture was stirred at room temperature overnight. The reaction solutionwas worked up by adding 200 ml of 2N of sodium hydroxide solution whilecooling, distilling out the solvent ethanol and diluting the remainingreaction mixture with water. It was extracted with diethyl ether (2×)and was washed with saturated sodium chloride solution (1×), and thecombined organic phases were dried over magnesium sulfate and filtered,and the solvent was removed in vacuo. The crude title compound wasobtained as a yellow oil which was then chromatographed on a 4 l suctionfunnel filled with silica gel using dichloromethane and 10% methanol aseluent. In total, 40 g (135 mmol, 53%) of tert-butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate were obtained.

b.1.2 1-Ethyl-4-piperidin-4-ylpiperazine as chloride salt

The protective group was removed by introducing 40 g (135 mmol) oftert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate fromexample b.1.1 into 200 ml of methanol and 1.8 l of dichloromethane andadding 100 ml of 5-6M HCl solution in isopropanol. A suspensionresulted, and slight gas evolution was also observable. The reactionmixture was stirred at 40° C. (water bath temperature) for one hour andthen stirred at room temperature for 48 hours. For completedeprotection, 50 ml of the 5-6M HCl solution in isopropanol were againadded and the reaction mixture was stirred at 40° C. The dichloromethanewas distilled out in a rotary evaporator. 200 ml of methanol and 30 mlof the 5-6M HCl solution in isopropanol were again added. The reactionmixture was stirred under reflux for one hour, during which a whitesuspension formed with strong evolution of gas. A mobile suspension thenresulted and was cooled to room temperature. The precipitate wasfiltered off with suction and washed with methanol and diethyl ether.After drying, 36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazinewere isolated as chloride salt.

¹H-NMR (D₂O, 400 MHz) δ[ppm]=3.74-3.47 (m, 11H), 3.28 (q, 2H, J=7.3 Hz),3.06 (dt, 2H, J=2.2 Hz, J=13.2 Hz), 2.38 (m, 2H, J=13.6 Hz), 1.89 (dq,2H, J=4.1 Hz, J=13.3 Hz), 1.30 (t, 3H, J=7.3 Hz).

II. Preparation of the Racemic Compounds of the Formula I

The compounds I of the invention were purified in some cases bypreparative HPLC, for example on a Prontosil Prep 2012, C18, 125×20 mm,5 μm column with a mobile phase gradient from 10% to 100% acetonitrilein water and 0.1% trifluoroacetic acid as modulator. The compounds Ithen result as trifluoroacetic acid salt.

II.1 Preparation of Racemic Compounds of the Formula I in which X¹ is NH(Examples 1 to 21) EXAMPLE 1(±)-4-(1-Methylpiperidin-4-yl)piperazin-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide1.1 3,5-Dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one

4.4 ml (54.3 mmol) of pyridine were added to a suspension of 13.3 g(43.6 mmol) of5-chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one fromexample a.1 in 50 ml of dichloromethane. After the reaction mixture hadbeen cooled to 0° C., 3.8 ml (52.3 mmol) of thionyl chloride was addeddropwise. The mixture was stirred at room temperature for one hour andthen poured into ice-water. After stirring for 15 minutes, the organicphase was separated off. The aqueous phase was extracted several timeswith dichloromethane. The combined organic phase was dried overmagnesium sulfate and filtered, and the solvent was removed in vacuo.15.6 g of the title compound were obtained as a yellowish solid whichwas employed without further purification in the next stage.

1.2 3-Amino-5-chloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one

104 ml (728 mmol) of a 7N methanolic ammonia solution were addeddropwise to a cooled solution of 47 g (145 mmol) of3,5-dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 250 mlof dichloromethane under a nitrogen atmosphere, and the reaction mixturewas then stirred at room temperature overnight. 250 ml of water and 250ml of dichloromethane were added to the reaction mixture. After stirringfor 5 min, a white solid was precipitated and filtered off and washedwith water and dichloromethane. Drying in a vacuum drying oven resultedin 26 g of the title compound as a white solid.

ESI-MS [M+H⁺]=304 (Cl isotope pattern)

1.33-Amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one

3.2 g (79 mmol) of sodium hydride (60% dispersion in mineral oil) wereadded in portions to a solution of 20 g (66 mmol) of3-amino-5-chloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 50ml of anhydrous dimethylformamide under a nitrogen atmosphere and whilecooling in an ice bath. The mixture was stirred at 0° C. for 10 min andthen 18.7 g (79 mmol) of 2,4-dimethoxybenzenesulfonyl chloride wereadded, and the mixture was stirred at room temperature for 30 min. Thereaction mixture was poured into ice-water and then extracted with ethylacetate. The organic phase was washed with saturated sodium chloridesolution and dried over magnesium sulfate, and the solvent wasevaporated. The residue was purified by chromatography on silica gel(120 g Redisep cartridge, mobile phase gradient from 2 to 25%dichloromethane in ethyl acetate). 34 g of the title compound wereobtained as a white solid.

ESI-MS [M+H⁺]=504 (Cl isotope pattern)

1.4 Phenyl[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate

0.83 ml (6.6 mmol) of phenyl chloroformate was slowly added dropwise toa solution, cooled to 0° C., of 2.57 g (5.1 mmol) of3-amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-onein 10 ml of dichloromethane and 4.1 ml of pyridine. The reaction mixturewas then stirred at room temperature overnight. The reaction mixture wasdiluted with dichloromethane and extracted with water. The organic phasewas washed with water and saturated sodium chloride solution, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in a little dichloromethane, and six times the volume ofdiisopropyl ether were added. The resulting precipitate was filteredoff, washed with diisopropyl ether and dried in vacuo. 3.01 g of thetitle compound were obtained as a white solid.

ESI-MS [M+H⁺]=624 (Cl isotope pattern).

1.54-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

A mixture of 800 mg (1.28 mmol) of phenyl[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate,470 mg (2.56 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 5 ml ofdried THF was stirred at room temperature for 24 hours. The reactionmixture was diluted with dichloro-methane and washed with water andsaturated sodium chloride solution, and the organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (12 g Redisep cartridge,mobile phase gradient from 2 to 12% methanol in dichloromethane). 790 mgof the title compound were obtained as a white solid.

ESI-MS [M+H⁺]=713 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.85 (1H), 7.70 (1H), 7.55(2H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H), 3.45 (3H),3.20 (4H), 2.75 (2H), 2.35 (4H), 2.10 (4H), 1.80 (2H), 1.65 (2H), 1.35(2H), 1.15 (3H).

The compounds of the formula I in which X¹ is NH according to examples 2to 21 can be prepared by using the appropriate 3-hydroxyoxindoles of theformula IV, sulfonyl chlorides of the formula VII and amines of theformula X in analogy to the process for preparing example 1.

EXAMPLE 2(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H]⁺=683 (Cl isotope pattern)

EXAMPLE 3(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt A-977409

ESI-MS [M+H⁺]=653 (Cl isotope pattern)

EXAMPLE 4(±)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.85 (1H), 7.70 (1H), 7.55(2H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H), 3.45 (3H),3.20 (4H), 2.85 (2H), 2.35 (4H), 2.30 (2H), 2.10 (1H), 1.80 (2H), 1.65(2H), 1.35 (2H), 1.10 (3H), 0.95 (3H).

EXAMPLE 5(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=713 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.90 (1H), 7.70 (1H), 7.60(1H), 7.55 (1H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.25 (2H), 3.85 (3H),3.80 (2H), 3.45 (3H), 2.65 (2H), 2.40 (4H), 2.30 (4H), 2.15 (3H), 1.60(2H), 1.15 (5H).

EXAMPLE 6(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=683 (Cl isotope pattern)

EXAMPLE 7(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=653 (Cl isotope pattern)

EXAMPLE 8(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.90 (1H), 7.70 (1H), 7.60(1H), 7.55 (1H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H),3.80 (2H), 3.45 (3H), 2.65 (2H), 2.25-2.50 (11H), 1.65 (2H), 1.15 (5H),0.95 (3H).

EXAMPLE 9(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=697 (Cl isotope pattern)

EXAMPLE 10(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=667 (Cl isotope pattern)

EXAMPLE 11(±)-[4,4′]Bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=698 (Cl isotope pattern)

EXAMPLE 12(±)-1′-Ethyl-[4,4′]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺ =726 (Cl isotope pattern)

EXAMPLE 13(±)-1′-Methyl-[4,4′]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=712 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.90 (1H), 7.70 (1H), 7.60(1H), 7.55 (1H), 7.40 (1H), 7.35 (1H), 7.00 (1H), 6.65 (2H), 4.20 (2H),3.90 (2H), 3.85 (3H), 3.45 (3H), 2.90 (2H), 2.55 (2H), 2.25 (3H), 2.05(2H), 1.55 (4H), 1.25 (3H), 1.15 (3H), 0.95 (3H).

EXAMPLE 14(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=9.64 (1H), 7.98 (1H), 7.93 (1H), 7.89(1H), 7.74 (1H), 7.40 (2H), 7.32 (1H), 6.75 (1H), 6.70 (1H), 4.20 (2H),3.88 (3H), 3.60 (2H), 3.48 (3H), 2.85-3.40 (9H), 2.80 (3H), 2.30 (2H),2.17 (3H), 1.80 (2H), 1.15 (3H).

EXAMPLE 15(±)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=741 (Cl isotope pattern)

EXAMPLE 16(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

EXAMPLE 17(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,trifluoroacetic acid salt

ESI-MS [M+H⁺]=741 (Cl isotope pattern)

EXAMPLE 18(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺ =727 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.85 (1H), 7.70 (1H), 7.60(1H), 7.50 (1H), 7.40 (1H), 7.35 (1H), 6.95 (1H), 6.70 (1H), 6.65 (1H),5.20 (1H), 3.85 (3H), 3.45 (3H), 3.20 (4H), 2.75 (2H), 2.35 (4H), 2.10(4H), 1.80 (2H), 1.65 (2H), 1.35 (2H), 1.20 (3H), 1.05 (3H).

EXAMPLE 19(±)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=741 (Cl isotope pattern)

EXAMPLE 20(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

EXAMPLE 21(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=741 (Cl isotope pattern)

II.2 Preparation of Racemic Compounds of the Formula I, in Which X¹ is O(Examples 22 to 27) EXAMPLE 225-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate,trifluoroacetic acid salt 22.1 Phenyl5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate

2.6 ml (21 mmol) of phenyl chloroformate were slowly added dropwise to asolution, cooled to 0° C., of 3.00 g (9.8 mmol) of5-chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one fromexample a.1 in 10 ml of pyridine, and the reaction mixture was stirredat room temperature overnight. The reaction mixture was diluted withdichloromethane and extracted with water. The organic phase was washedwith water and saturated sodium chloride solution, dried over magnesiumsulfate and concentrated under reduced pressure. The residue was stirredwith diethyl ether. 2.58 g of the title compound were obtained as awhite solid.

ESI-MS [M+H⁺]=545 (Cl isotope pattern).

22.2 5-Chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

A mixture of 1.29 g (2.37 mmol) of phenyl5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate,1.73 g (9.46 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 10 ml ofdry THF was stirred at room temperature for 72 hours. The reactionmixture was diluted with dichloromethane and extracted with water andsaturated sodium chloride solution. The organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas stirred with diethyl ether. 963 mg of the title compound wereobtained as a white solid.

ESI-MS [M+H⁺]=514 (Cl isotope pattern).

22.35-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroacetic acidsalt

7.5 mg (0.19 mmol) of sodium hydride (60% dispersion in mineral oil)were added to a solution of 80 mg (0.16 mmol) of5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of anhydrousdimethylformamide under a nitrogen atmosphere and while cooling in anice bath. The mixture was stirred at 0° C. for 10 min and then 44 mg(0.19 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were added, and themixture was stirred at room temperature for a further 30 min. Thereaction mixture was poured into ice-water and then extracted with ethylacetate. The organic phase was washed with saturated sodium chloridesolution and dried over magnesium sulfate, and the solvent wasevaporated. The residue was purified by preparative HPLC (Prontosil Prep2012, C18, 125×20 mm, 5 μm, gradient from 10% to 100% acetonitrile inwater, 0.1% trifluoroacetic acid). 78 mg of the title compound wereobtained as a white solid.

ESI-MS [M+H⁺]=714 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=9.60 (1H), 8.20 (1H), 8.15 (1H), 7.85(1H), 7.80 (1H), 7.50 (1H), 7.20 (1H), 7.10 (1H), 6.70 (2H), 4.10 (2H),3.85 (3H), 3.55 (3H), 2.90-3.50 (11H), 2.75 (3H), 2.15 (2H), 1.75 (2H),1.00 (3H).

The compounds of the formula I in which X¹ is O, according to examples23 to 27, can be prepared using the appropriate 3-hydroxyoxindoles ofthe formula IV, sulfonyl chlorides of the formula VII and amines of theformula X in analogy to the process for preparing example 22.

EXAMPLE 235-Chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroaceticacid salt

ESI-MS [M+H⁺]=684 (Cl isotope pattern)

EXAMPLE 241-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroaceticacid salt

ESI-MS [M+H⁺]=654 (Cl isotope pattern)

EXAMPLE 255-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate, trifluoroaceticacid salt

ESI-MS [M+H⁺]=714 (Cl isotope pattern)

EXAMPLE 265-Chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate, trifluoroaceticacid salt

ESI-MS [M+H⁺]=684 (Cl isotope pattern)

EXAMPLE 271-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate, trifluoroaceticacid salt

ESI-MS [M+H⁺]=654 (Cl isotope pattern)

II.3 Preparation of Racemic Compounds of the Formula I in which X¹ isCH₂ (Examples 28 to 33) EXAMPLE 28(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt 28.1 Dimethyl2-[5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-malonate

11.2 ml (98 mmol) of dimethyl malonate were slowly added dropwise to asuspension, cooled to 10° C., of 3.56 g (89 mmol) of sodium hydride (60%dispersion in mineral oil) in 150 ml of dimethylformamide, and themixture was then stirred at room temperature for 30 minutes.Subsequently, 9.6 g (30 mmol) of3,5-dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one fromexample 1.1 were added in portions, and the mixture was stirred at roomtemperature for 15 min. To work up the reaction it was stirred into cold1N HCl, and dichloromethane was added. The phases were separated, andthe aqueous phase was extracted with dichloromethane. The combinedorganic phase was washed with water and saturated sodium chloridesolution and dried over magnesium sulfate, and the solvent was removedin vacuo. The residue was recrystallized from dichloromethane/pentane.9.01 g of the title compound were obtained as a yellowish solid.

ESI-MS [M+H⁺]=419 (Cl isotope pattern).

28.2 Methyl[5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate

Hydrolysis: 90 ml of 2N sodium hydroxide solution were added to asolution of 9.00 g (21.5 mmol) of dimethyl2-[5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]malonatein 9 ml of ethanol, and the mixture was stirred at room temperature forone hour. The mixture was poured into ice-cold 1N hydrochloric acidwhile stirring, and the mixture was extracted with dichloromethaneseveral times. The combined organic phase was washed with water andsaturated sodium chloride solution and dried over magnesium sulfate, andthe solvent was removed in vacuo. The yellowish solid resultingtherefrom (8.41 g of mixture of diastereomers) was dried in a vacuumdrying oven at 40° C.

Decarboxylation: The hydrolysis product (8.41 g) obtained above washeated in a one-necked flask under a blanket of nitrogen to 150° C.After evolution of CO₂ ceased, the reaction mixture was allowed to coolto room temperature and the residue was stirred with methanol. Crystalsformed and were stored in a refrigerator overnight. 5.25 g of the titlecompound were obtained as a yellowish solid.

ESI-MS [M+H⁺]=361 (Cl isotope pattern).

28.3[5-Chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]aceticacid

20 ml of water and 10 ml of 2N sodium hydroxide solution were added to asolution of 1.96 g (5.43 mmol) of methyl[5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetatein 10 ml of ethanol. The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was worked up by adjusting to pH 5with 1N hydrochloric acid and then concentrating in a rotary evaporator.The residue was taken up in toluene and again evaporated to dryness, andthe residue was dried in a vacuum drying oven. 3.75 g of crude productwere obtained and were employed without further purification in the nextstage.

ESI-MS [M+H⁺]=347 (Cl isotope pattern).

28.45-Chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one

195 mg (1.44 mmol) of 1-hydroxybenzotriazole and 276 mg (1.44 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were addedto a solution of 1.00 g of[5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]aceticacid in 10 ml of dimethylformamide and, after stirring for 15 minutes,277 mg (1.51 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 1.00 ml(7.41 mmol) of triethylamine were added. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was mixedwith water and extracted with ethyl acetate several times. The combinedorganic phase was extracted with water and saturated sodium chloridesolution and dried over magnesium sulfate, and the solvent wasconcentrated in vacuo. The residue was purified by chromatography onsilica gel (12 g Redisep cartridge, mobile phase gradient from 10 to 70%methanol in dichloromethane). 311 mg of the title compound were obtainedas a white foam.

ESI-MS [M+H⁺]=512 (Cl isotope pattern).

28.55-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt

6.6 mg (0.16 mmol) of sodium hydride (60% dispersion in mineral oil)were added to a solution of 70 mg (0.14 mmol) of5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-onein 2 ml of dimethylformamide under a nitrogen atmosphere and whilecooling in an ice bath. The reaction mixture was stirred at 0° C. for 10min and then 39 mg (0.16 mmol) of 2,4-dimethoxybenzenesulfonyl chloridewere added, and the mixture was stirred at room temperature for 30 min.The reaction mixture was poured into ice-water and then extracted withethyl acetate. The organic phase was washed with saturated sodiumchloride solution and dried over magnesium sulfate, and the solvent wasevaporated. The residue was purified by preparative HPLC (Prontosil Prep2012, C18, 125×20 mm, 5 μm, gradient from 10% to 100% acetonitrile inwater, 0.1% trifluoroacetic acid). 45 mg of the title compound wereobtained as a white solid.

ESI-MS [M+H⁺]=712 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=10.25 (1H), 8.10 (1H), 7.90 (2H),7.80 (1H), 7.35 (1H), 7.20 (1H), 7.00 (1H), 6.65 (2H), 4.10 (2H), 3.95(2H), 3.85 (3H), 3.60 (3H), 3.55 (2H), 2.90-3.50 (11H), 2.75 (3H), 2.25(2H), 1.90 (2H), 1.00 (3H).

The compounds of the formula I in which X¹ is CH₂, according to examples29 to 33, can be prepared using the appropriate sulfonyl chlorides ofthe formula VII and amines of the formula X in analogy to the processfor preparing example 28.

EXAMPLE 29(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt

ESI-MS [M+H⁺]=652 (Cl isotope pattern)

EXAMPLE 30(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt

ESI-MS [M+H⁺]=712 (Cl isotope pattern)

EXAMPLE 31(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt

ESI-MS [M+H⁺]=652 (Cl isotope pattern)

EXAMPLE 32(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt

ESI-MS [M+H⁺]=726 (Cl isotope pattern)

EXAMPLE 33(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one,trifluoroacetic acid salt

ESI-MS [M+H⁺]=666 (Cl isotope pattern)

III. Preparation of the Chiral Compounds of the Formula I

Racemic compounds of the formula I can be resolved for example byseparation on a preparative chiral column.

EXAMPLE 1A AND EXAMPLE 1B Racemate Resolution of(±)-4-(1-methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

100 mg of racemic4-(1-methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamidefrom example 1 were resolved on a chiral preparative column (ChiralcellOD, flow rate 55 ml/min) with n-heptane/ethanol (7:3) as eluent. Yield:33 mg of the levorotatory enantiomer (example 1A) and 27 mg of thedextrorotatory enantiomer (example 1B).

EXAMPLE 1A(−)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=713 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.85 (1H), 7.70 (1H), 7.55(2H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H), 3.45 (3H),3.20 (4H), 2.75 (2H), 2.35 (4H), 2.10 (4H), 1.80 (2H), 1.65 (2H), 1.35(2H), 1.15 (3H).

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=7.4 min

[α]²⁰ _(D)=−16 (c 0.1, CHCl₃)

EXAMPLE 1B(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=713 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.85 (1H), 7.70 (1H), 7.55(2H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H), 3.45 (3H),3.20 (4H), 2.75 (2H), 2.35 (4H), 2.10 (4H), 1.80 (2H), 1.65 (2H), 1.35(2H), 1.15 (3H).

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=20.0 min

[α]²⁰ _(D)=+12 (c 0.1, CHCl₃)

The racemates of EXAMPLES 4, 5 and 8 can be resolved in an analogousmanner to obtain the corresponding enantiomers.

EXAMPLE 4B(+)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.85 (1H), 7.70 (1H), 7.55(2H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H), 3.45 (3H),3.20 (4H), 2.85 (2H), 2.35 (4H), 2.30 (2H), 2.10 (1H), 1.80 (2H), 1.65(2H), 1.35 (2H), 1.10 (3H), 0.95 (3H).

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=17.9 min

[α]²⁰ _(D)=+12 (c 0.1, CHCl₃)

EXAMPLE 5A(−)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=713 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.90 (1H), 7.70 (1H), 7.60(1H), 7.55 (1H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.25 (2H), 3.85 (3H),3.80 (2H), 3.45 (3H), 2.65 (2H), 2.40 (4H), 2.30 (4H), 2.15 (3H), 1.60(2H), 1.15 (5H).

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=7.6 min

[α]²⁰ _(D)=−14 (c 0.1, CHCl₃)

EXAMPLE 5B(+)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=713 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.90 (1H), 7.70 (1H), 7.60(1H), 7.55 (1H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.25 (2H), 3.85 (3H),3.80 (2H), 3.45 (3H), 2.65 (2H), 2.40 (4H), 2.30 (4H), 2.15 (3H), 1.60(2H), 1.15 (5H).

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=12.2 min

[α]²⁰ _(D)=+9 (c 0.1, CHCl₃)

EXAMPLE 8B(+)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS [M+H⁺]=727 (Cl isotope pattern)

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.10 (1H), 7.90 (1H), 7.70 (1H), 7.60(1H), 7.55 (1H), 7.35 (2H), 6.95 (1H), 6.65 (2H), 4.20 (2H), 3.85 (3H),3.80 (2H), 3.45 (3H), 2.65 (2H), 2.25-2.50 (11H), 1.65 (2H), 1.15 (5H),0.95 (3H).

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=11.5 min

[α]²⁰ _(D)=+20 (c 0.1, CHCl₃)

IV. Determination of the Biological Activity

1. Vasopressin V1b Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSOand further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M. These serial DMSOpredilutions were diluted 1:10 with assay buffer. The substanceconcentration was further diluted 1:5 in the assay mixture (2% DMSO inthe mixture).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini #1836170) using aPolytron homogenizer at intermediate setting for 2×10 seconds, andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and subsequently taken upin 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen inliquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_(—)3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 M AVP (Bachem#H1780). All determinations were carried out as triplicatedeterminations. After incubation (60 minutes at room temperature), thefree radioligand was filtered off by vacuum filtration (Skatron cellharvester 7000) through Wathman GF/B glass fiber filter mats, and thefilters were transferred into scintillation vials. The liquidscintillation measurement took place in a model 2000 or 2200CA Tricarbinstrument (Packard). Conversion of the measured cpm into dpm wascarried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4nM and was used to determine the Ki.

2. Vasopressin V1a Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.Further dilution of these DMSO solutions took place in incubation buffer(50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and subsequently taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (20 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a_(—)5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mMMgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem #H1780).Triplicate determinations were carried out. After incubation (60 minutesat room temperature), the free radioligand was filtered off by vacuumfiltration (Skatron cell harvester 7000) through Wathman GF/B glassfiber filter mats, and the filters were transferred into scintillationvials.

The liquid scintillation measurement took place in a model 2000 or2200CA Tricarb instrument (Packard). Conversion of the measured cpm intodpm was carried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki.

3. Vasopressin V2 Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.Further dilution of these DMSO solutions took place in incubation buffer(50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone23) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and subsequently taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V2 receptors (cellline hV2_(—)23_CHO) were incubated with 1-2 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP(Bachem #H1780). Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Skatron cell harvester 7000)through Wathman GF/B glass fiber filter mats, and the filters weretransferred into scintillation vials.

The liquid scintillation measurement took place in a model 2000 or2200CA Tricarb instrument (Packard). Conversion of the measured cpm intodpm was carried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant hV2 receptors is 2.4 nMand was used to determine the Ki.

4. Oxytocin receptor binding assay

Substances:

The substances were dissolved in a concentration of 10⁻² M in DMSO anddiluted with incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH7.4).

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g at room temperature for 5minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor)and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzedcells were then centrifuged at 750×g at 4° C. for 20 minutes, theresidue was taken up in incubation buffer, and aliquots of 10⁷ cells/mlwere prepared. The aliquots were frozen at −80° C. until used.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted withincubation buffer and homogenized using a Multipette Combitip(Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2to 5×10⁴ recombinant cells, 3-4 nM ³H-oxytocin (PerkinElmer, NET 858) inthe presence of test substance (inhibition plot) or only incubationbuffer (total binding). The nonspecific binding was determined with 10⁻⁶M oxytocin (Bachem AG, H2510). Triplicate determinations were set up.Bound and free radioligand were separated by filtration under vacuumwith Whatman GF/B glass fiber filters with the aid of a Skatron cellharvester 7000. The bound radioactivity was determined by liquidscintillation measurement in a Tricarb Beta counter, model 2000 or2200CA (Packard).

Analysis:

The binding parameters were calculated by nonlinear regression analysis(SAS) in analogy to the LIGAND program of Munson and Rodbard (AnalyticalBiochem 1980; 107: 220-239). The Kd of ³H-oxytocin for the recombinanthOT receptors is 7.6 nM and was used to determine the Ki.

5. Determination of the microsomal half-life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows: 0.5 μM test substance are preincubated together with livermicrosomes from different species (from rat, human or other species)(0.25 mg of microsomal protein/mi) in 0.05 M potassium phosphate bufferof pH 7.4 in microtiter plates at 37° C. for 5 min. The reaction isstarted by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50μl aliquots are removed, and the reaction is immediately stopped andcooled with the same volume of acetonitrile. The samples are frozenuntil analyzed. The remaining concentration of undegraded test substanceis determined by MSMS. The half-life (T1/2) is determined from thegradient of the signal of test substance/unit time plot, it beingpossible to calculate the half-life of the test substance, assumingfirst order kinetics, from the decrease in the concentration of thecompound with time. The microsomal clearance (mCl) is calculated frommCl=In2/T1/2/(content of microsomal protein in mg/ml)×1000 [ml/min/mg](modified from references: Di, The Society for Biomoleculur Screening,2003, 453-462; Obach, DMD, 1999 vol 27. N 11, 1350-1359).

6. Methods for in vitro determination of the cytochrome P450 (CYP)inhibition

Luminescent Substrates for 2C9 and 3A4:

0.4 mg/ml human liver microsomes are preincubated with the testsubstances to be investigated (0-20 μM), the CYP-specific substrates, in0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. TheCyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 isluciferin BE. The reaction is started by adding NADPH. After incubationat RT for 30 min, the luciferin detection reagent is added, and theresulting luminescence signal is measured (modified from reference:Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 time-dependent inhibition

The assay consists of 2 parts. Firstly, the test substance ispreincubated with the liver microsomes (with NADPH=preincubation, thenaddition of the substrate; in the second part the substrate and the testsubstance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 0-10 μM (or 50 μM) test substance in 50 mM potassium phosphatebuffer for 5 min. The reaction is started with NADPH. After 30 min 4 μMmidazolam (final concentration) are added, and incubation is continuedfor 10 min. 75 μl of the reaction solution are removed after 10 min, andstopped with 150 μl of acetonitrile solution.

Coincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 4 μm midazolam (final concentration) and 0-10 μM (or 50 μM) testsubstance in 50 mM potassium phosphate buffer for 5 min. The reaction isstarted with NADPH. 75 μl of the reaction solution are removed after 10min and stopped with 150 μl of acetonitrile solution. The samples arefrozen until the MSMS analysis (modified from references: Obdach,Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1,336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6,647-660, 2004).

7. Method for determining the solubility in water (in mg/ml)

The solubility in water of the compounds of the invention can bedetermined for example by the so-called shake flask method (as specifiedin ASTM International: E 1148-02, Standard test methods for measurementof aqueous solubility, Book of Standards Volume 11.05.). This entails anexcess of the solid compound being put into a buffer solution with aparticular pH (for example phosphate buffer of pH 7.4), and theresulting mixture being shaken or stirred until equilibrium has been setup (typically 24 or 48 hours, sometimes even up to 7 days). Theundissolved solid is then removed by filtration or centrifugation, andthe concentration of the dissolved compound is determined by UVspectroscopy or high pressure liquid chromatography (HPLC) by means ofan appropriate calibration plot.

8. Results

The results of the receptor binding investigations are expressed asreceptor binding constants [K_(i)(V1b)] or selectivities[K_(i)(V1a)/K_(i)(V1b)]. The results of the investigation of themetabolic stability are indicated as microsomal clearance (mCl).

The compounds of the invention show very high affinities for the V1breceptor in these assays (maximally 100 nM, or maximally 10 nM,frequently <1 nM). The compounds also show high selectivities vis-à-visthe V1a receptor and a good metabolic stability, measured as microsomalclearance.

The results are listed in table 2. The numbers of the compounds refer tothe synthesis examples.

TABLE 2 Human microsomal K_(i) (h-V1b)* K_(i) (h-V1a)/ clearance Example[nM] K_(i) (h-V1b)* [μl min⁻¹ mg⁻¹]  1 +++ +++ +  3 ++ ++ +++ 13 +++++ + 14 +++ +++ ++ 15 +++ ++ + 16 +++ + + 17 +++ + + 24 ++ ++ ++ 28 +++++ + 29 ++ + +++ 32 +++ + ++ 1B +++ +++ +++ 4B +++ +++ ++ 5B +++ +++ +++8B +++ +++ + *h = human Key: K_(i) (h-V1a)/ Human microsomal K_(i) (V1b)K_(i) (h-V1b) clearance + >10-100 nM   10-<25 >75-100 μl min⁻¹ mg⁻¹ ++1-10 nM 25-75 50-75 μl min⁻¹ mg⁻¹ +++ <1 nM >75 <50 μl min⁻¹ mg⁻¹

The invention claimed is:
 1. A compound of the formula I

in which R¹ is hydrogen, methoxy or ethoxy; R² is hydrogen or methoxy;R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl; R⁴ is ethoxy orisopropoxy; R⁵ is H or methyl; R⁶ is Cl or F; X¹ is O, NH or CH₂; and X²and X³ are N or CH, with the proviso that X² and X³ are notsimultaneously N; a racemate thereof, an enantiomeric, or apharmaceutically acceptable salt of thereof.
 2. A compound of claim 1,in which R¹ is hydrogen or methoxy.
 3. A compound of claim 1, in whichR¹ and R² are methoxy.
 4. A compound claim 1, in which R³ is hydrogen,methyl or ethyl.
 5. A compound of claim 1, in which R⁴ is ethoxy and R⁵is H.
 6. A compound of claim 1, in which R⁴ is ethoxy and R⁵ is methyl.7. A compound of claim 1, in which R⁴ is isopropoxy and R⁵ is H.
 8. Acompound of claim 1, in which R⁶ is Cl.
 9. A compound of claim 1, inwhich R⁶ is F.
 10. A compound of claim 1, in which X² is N and X³ is CH.11. A compound of claim 1, in which X² is CH and X³ is N.
 12. A compoundof claim 1, in which X¹ is O.
 13. A compound of claim 1, in which X¹ isNH.
 14. A compound of claim 1, in which X¹ is CH₂.
 15. A compound ofclaim 1, in which R¹ is methoxy; R² is methoxy; R³ is methyl; R⁴ isethoxy; R⁵ is H; R⁶ is Cl; X¹ is NH; X² is N; and X³ is CH.
 16. Acompound of claim 1, in which R¹ is methoxy; R² is methoxy; R³ ismethyl; R⁴ is ethoxy; R⁵ is methyl; R⁶ is Cl; X¹ is NH; X² is N; and X³is CH.
 17. A compound of claim 1, in which R¹ is methoxy; R² is methoxy;R³ is ethyl; R⁴ is ethoxy; R⁵ is H; R⁶ is Cl; X¹ is NH; X² is N; and X³is CH.
 18. A compound of claim 1, in which R¹ is methoxy; R² is methoxy;R³ is methyl; R⁴ is ethoxy; R⁵ is H; R⁶ is Cl; X¹ is NH; X² is CH; andX³ is N.
 19. A compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of:(±)-4-(1-Methylpiperidin-4-yl)piperazin-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-[4,4′]Bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-y1)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-1′-Ethyl-[4,4″]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-1′-Methyl-[4,41]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(±)-4-(1-Ethylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-5-methylpyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;(±)-4-(1-Methylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;(±)-4-(1-Ethylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;(±)-4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;(±)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-isopropoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide;5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(1-methylpiperidin-4-Apiperazine-1-carboxylate;5-Chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(1-methylpiperidin-4-Apiperazine-1-carboxylate;1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate;5-Chloro-3-(2-ethoxypyridin-3-yl)-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indo1-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate;1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl(±)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate;(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1 -yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindol-2-one;(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;(±)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;(±)-1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-3-{2-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-dihydroindo1-2-one;(−)4(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(+)-4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;and (+)4 (4Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.20. A pharmaceutical composition comprising at least one compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof, andat least one pharmaceutically acceptable carrier.
 21. A method for thetreatment of a disease selected from the group consisting of arterialhypertension and congestive heart failure (CHF), the method comprisingadministering a compound of claim 1 or a pharmaceutically acceptablesalt thereof to a subject in need thereof.
 22. A method for thetreatment of major depression, the method comprising administering acompound of claim 1 or a pharmaceutically acceptable salt thereof to asubject in need thereof.
 23. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein the compound is(+)-4-(1-Methylpiperidin-4-Apiperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.24. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound is(+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.25. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound is(+)-4-(4-Ethylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide.26. The pharmaceutical composition of claim 20, wherein the compound is(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 27. The pharmaceuticalcomposition of claim 20, wherein the compound is(+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 28. The pharmaceuticalcomposition of claim 20, wherein the compound is(+)-4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 29. The method of claim21, wherein the compound is(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indo1-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 30. The method of claim21, wherein the compound is(+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 31. The method of claim21, wherein the compound is(+)-4-(4-Ethylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 32. The method of claim22, wherein the compound is(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 33. The method of claim22, wherein the compound is(+)-4-(4-Methylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.
 34. The method of claim22, wherein the compound is(+)-4-(4-Ethylpiperazin-1-Apiperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide,or a pharmaceutically acceptable salt thereof.